Submissions for variant NM_024747.6(HPS6):c.1114C>T (p.Arg372Ter)

gnomAD frequency: 0.00001  dbSNP: rs776754431

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867540	SCV002131812	pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Gln680*) have been determined to be pathogenic (PMID: 27225848). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1368527). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 27641950). This variant is present in population databases (rs776754431, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg372*) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the HPS6 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801068	SCV005422483	pathogenic	Hermansky-Pudlak syndrome	2024-10-10	criteria provided, single submitter	clinical testing	Variant summary: HPS6 c.1114C>T (p.Arg372X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250230 control chromosomes. c.1114C>T has been reported in the literature in a homozygous individual and a compound heterozygous individual affected with Hermansky-Pudlak Syndrome (O'Brien_2016, Zhou_2024). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27641950, 38091959). Multiple downstream truncating variants have been reported in individuals with Hermansky-Pudlak Syndrome and have been classified as pathogenic or likely pathogenic. ClinVar contains an entry for this variant (Variation ID: 1368527). Based on the evidence outlined above, the variant was classified as pathogenic.